Metabolon formation regulates branched-chain amino acid oxidation and homeostasis

Patrick, McKenzie; Gu, Zhimin; Zhang, Gen; Wynn, R. Max; Kaphle, Pranita; Cao, Hui; Vu, Hieu; Cai, Feng; Gao, Xiaofei; Zhang, Yuannyu; Chen, Mingyi; Ni, Min; Chuang, David T.; DeBerardinis, Ralph J.; Xu, Jian

doi:10.1038/s42255-022-00689-4

Cited by 20 publications

(9 citation statements)

References 61 publications

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“…Still, caution should be taken to not fully deplete DBT levels in BCKDK deficiency, as the loss of DBT function would lead to a Maple-Syrup Urine Disease (MSUD), which induces severe neurological dysfunction [ 2 ]. Dbt haploinsufficiency may modulate this pathway by additional mechanisms by reducing BCAT activity, as they have been shown to interact in a metabalon [ 29 ]. This further illustrates that BCAA catabolism is fine-tuned to maintain metabolic homeostasis and neurodevelopment.…”

Section: Discussionmentioning

confidence: 99%

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency

Ohl,

Kuhs,

Pluck

et al. 2024

Molecular Genetics and Metabolism Reports

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Section: Discussionmentioning

confidence: 99%

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency

Ohl,

Kuhs,

Pluck

et al. 2024

Molecular Genetics and Metabolism Reports

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“…This reallocation is facilitated by the upregulation of all mitochondrial enzymes in the pathway and the translocation of BCAT2 from the cytosol to the mitochondria. Indeed, previous studies have demonstrated that BCAT2 assembles with downstream mitochondrial enzymes into a metabolome complex and may enhance flux through the mitochondrial portion of the pathway 48 .…”

Section: Discussionmentioning

confidence: 99%

A spatiotemporal proteomic map of human adipogenesis

Klingelhuber,

Frendo-Cumbo,

Omar-Hmeadi

et al. 2024

Nat Metab

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White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic disorders; however, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, we generate a spatiotemporal proteomic atlas of human adipogenesis, which elucidates cellular remodelling as well as the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipocyte formation. We identify compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogramme branched-chain amino acids and one-carbon metabolism to provide building blocks and reduction equivalents. Additionally, we identify C19orf12 as a differentiation-induced adipocyte lipid droplet protein that interacts with the translocase of the outer membrane complex of lipid droplet-associated mitochondria and regulates adipocyte lipid storage by determining the capacity of mitochondria to metabolize fatty acids. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field.

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“…Still, caution should be taken to not fully deplete DBT levels in BCKDK deficiency, as the loss of DBT function would lead to a Maple-Syrup Urine Disease (MSUD), which induces severe neurological dysfunction 2 . Dbt haploinsufficiency may modulate this pathway by additional mechanisms by reducing BCAT activity, as they have been shown to interact in a metabalon 24 . This further illustrates that BCAA catabolism is fine-tuned to maintain metabolic homeostasis and neurodevelopment.…”

Section: Discussionmentioning

confidence: 99%

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency

Ohl,

Kuhs,

Pluck

et al. 2023

Preprint

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Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, throughDbthaploinsufficiency, partially rescued biochemical and behavioral phenotypes in BCKDK deficient mice. Collectively, these data raise into question assumptions widely made about the pathophysiology of BCKDK insufficiency and suggest a novel approach to develop potential therapies for this disease.

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Metabolon formation regulates branched-chain amino acid oxidation and homeostasis

Cited by 20 publications

References 61 publications

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency

A spatiotemporal proteomic map of human adipogenesis

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency

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